Epac2 mediates cardiac β1-adrenergic-dependent sarcoplasmic reticulum Ca2+ leak and arrhythmia

Laëtitia Pereira, Hongqiang Cheng, Dieu Hung Lao, Li Na, Ralph J. Van Oort, Joan Heller Brown, Xander H T Wehrens, Ju Chen, Donald M Bers

Research output: Contribution to journalArticlepeer-review

110 Scopus citations


BACKGROUND - : β-Adrenergic receptor (β-AR) activation can provoke cardiac arrhythmias mediated by cAMP-dependent alterations of Ca signaling. However, cAMP can activate both protein kinase A and an exchange protein directly activated by cAMP (Epac), but their functional interaction is unclear. In heart, selective Epac activation can induce potentially arrhythmogenic sarcoplasmic reticulum (SR) Ca release that involves Ca/calmodulin-dependent protein kinase II (CaMKII) effects on the ryanodine receptor (RyR). METHODS AND RESULTS - : We tested whether physiological β-AR activation causes Epac-mediated SR Ca leak and arrhythmias and whether it requires Epac1 versus Epac2, β1-AR versus β2-AR, and CaMKIIδ-dependent phosphorylation of RyR2-S2814. We used knockout (KO) mice for Epac1, Epac2, or both. All KOs exhibited unaltered basal cardiac function, Ca handling, and hypertrophy in response to pressure overload. However, SR Ca leak induced by the specific Epac activator 8-CPT in wild-type mice was abolished in Epac2-KO and double-KO mice but was unaltered in Epac1-KO mice. β-AR-induced arrhythmias were also less inducible in Epac2-KO versus wild-type mice. β-AR activation with protein kinase A inhibition mimicked 8-CPT effects on SR Ca leak and was prevented by blockade of β1-AR but not β2-AR. CaMKII inhibition (KN93) and genetic ablation of either CaMKIIδ or CaMKII phosphorylation on RyR2-S2814 prevented 8-CPT-induced SR Ca leak. CONCLUSIONS - : β1-AR activates Epac2 to induce SR Ca leak via CaMKIIδ-dependent phosphorylation of RyR2-S2814. This pathway contributes to β-AR-induced arrhythmias and reduced cardiac function.

Original languageEnglish (US)
Pages (from-to)913-922
Number of pages10
Issue number8
StatePublished - 2013


  • adrenergic
  • arrhythmias
  • calcium
  • cardiac
  • heart failure
  • receptors
  • sarcoplasmic reticulum

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine


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